Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 930
Filtrar
1.
J Pharm Biomed Anal ; 177: 112851, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31499427

RESUMO

A high performance liquid chromatographic method was developed for the simultaneous determination of the related substances (R-ivabradine, dehydro-S-ivabradine, N-demethyl-S-ivabradine, ((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-yl-methyl)-methyl-amine) and 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-on-3-yl)-3-chloro-propane) of the heart-rate lowering drug, ivabradine. The separation capability of seven different polysaccharide-type chiral columns (Lux Amylose-1, Lux i-Amylose-1, Lux Amylose-2, Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-3 and Lux Cellulose-4) was investigated with a mobile phase consisting of 0.1% diethylamine in methanol, 2-propanol and acetonitrile. During the screnning experiments the best results were obtained on Lux Cellulose-2 (based on cellulose tris(3-chloro-4-methylphenylcarbamate) column with methanol with an ideal case, where all the impurities eluted before the S-ivabradine peak. Chromatographic parameters (flow rate, temperature and mobile phase constituents) were optimized by a full factorial screening design. Using optimized parameters (Lux Cellulose-2 column with 0.06% (v/v) diethylamine in methanol/acetonitrile 98/2 (v/v) with 0.45 mL/min flow rate at 12 °C) baseline separations were achieved between all compounds. The optimized method was validated according to the International Council on Harmonization Q2(R1) guideline and proved to be reliable, linear, precise and accurate for determination of at least 0.05% for all impurities in S-ivabradine samples. Method application was tested on a commercial tablet formulation and proved to be suitable for routine quality control of both chiral and achiral related substances of S-ivabradine.


Assuntos
Composição de Medicamentos/normas , Contaminação de Medicamentos/prevenção & controle , Ivabradina/análise , Controle de Qualidade , Celulose/análogos & derivados , Celulose/química , Química Farmacêutica , Cromatografia Líquida de Alta Pressão/instrumentação , Ivabradina/química , Fenilcarbamatos/química , Estereoisomerismo , Comprimidos , Temperatura Ambiente
2.
Kardiologiia ; 59(10): 60-65, 2019 Oct 14.
Artigo em Russo | MEDLINE | ID: mdl-31615388

RESUMO

Ischemic heart disease (IHD) and chronic heart failure (CHF) belong to leading causes of death among patients with cardiovascular diseases (CVD). Modern medical approaches to the treatment of patients with CHF do not always provide a significant improvement in the quality of life, a decrease in the frequency of CHF exacerbations and hospitalizations, and an improvement of the long-term prognosis. According to the neurohumoral theory of IHD and CHF development, the blockade of the sympathoadrenal system with ß-adrenoblockers (ß-AB) is pathogenetically substantiated, and preparations of this group are recommended as one of the main classes of drugs for the treatment of patients with CHF. However, selection of heart rhythm slowing therapy in patients with CHF of ischemic genesis is often difficult due to the development of undesirable side effects of ß-AB, intolerance and/or due to the presence of contraindications for their use. Randomized studies have shown that prescribing a combination of ß-AB and If-channel blocker ivabradine for heart rate (HR) reduction or solely ivabradine when use of ß-AB is impossible in complex CHF therapy, improves the left ventricle (LV) diastolic function, reducing mortality from CHF decompensation. However, the prognostic significance of the use of ivabradine in patients with CHF with preserved left ventricular ejection fraction of ischemic genesis with heart rate higher than 70 beats/min receiving maximum tolerated doses of ß-AB remains not fully investigated.


Assuntos
Insuficiência Cardíaca , Isquemia Miocárdica , Frequência Cardíaca , Humanos , Ivabradina , Qualidade de Vida
3.
Med Hypotheses ; 129: 109253, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31371087

RESUMO

Ivabradine decreases heart rate by selective inhibition of the If current in the sinoatrial node. Ivabradine is declared to have no direct effect on the autonomic nervous system (ANS). However, there are some data suggesting an (at least indirect) effect of ivabradine on the ANS. The pathomechanism behind is unclear. Based on the complex of plexuses and ganglia in the heart, the existence of the intrinsic cardiac nervous system (ICNS), also known as the "little brain" of the heart, has been suggested. The ICNS is supposed to process information on the cardiac milieu and provide the central nervous system with these data. We put forward a hypothesis that part of ivabradine's protective effects might reside in the modulation of the ANS by affecting the ICNS. Setting a new autonomic balance by ivabradine might be of benefit in the treatment of autonomic dysfunction-related pathologies.


Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Ivabradina/farmacologia , Nó Sinoatrial/efeitos dos fármacos , Animais , Doenças do Sistema Nervoso Autônomo/tratamento farmacológico , Fármacos Cardiovasculares , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Modelos Teóricos , Ratos
4.
Curr Top Med Chem ; 19(21): 1878-1901, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31400267

RESUMO

Chronic Heart Failure (CHF) is a complex clinical syndrome with a high incidence worldwide. Although various types of pharmacological and device therapies are available for CHF, the prognosis is not ideal, for which, the control of increased Heart Rate (HR) is critical. Recently, a bradycardic agent, ivabradine, is found to reduce HR by inhibiting the funny current (If). The underlying mechanism states that ivabradine can enter the Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and bind to the intracellular side, subsequently inhibiting the If. This phenomenon can prolong the slow spontaneous phase in the diastolic depolarization, and thus, reduce HR. The clinical trials demonstrated the significant effects of the drug on reducing HR and improving the symptoms of CHF with fewer adverse effects. This review primarily introduces the chemical features and pharmacological characteristics of ivabradine and the mechanism of treating CHF. Also, some expected therapeutic effects on different diseases were also concluded. However, ivabradine, as a typical If channel inhibitor, necessitates additional research to verify its pharmacological functions.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Ivabradina/uso terapêutico , Animais , Fármacos Cardiovasculares/química , Doença Crônica , Humanos , Ivabradina/química , Estrutura Molecular
5.
J Chromatogr A ; 1608: 460407, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31383356

RESUMO

A chiral methodology was developed for the first time to ensure the quality control of ivabradine, a novel anti-ischemic and heart rate lowering drug commercialized as a pure enantiomer. With this aim, electrokinetic chromatography (EKC) was employed and the enantiomeric separation of ivabradine was investigated using different anionic and neutral cyclodextrins (CDs) and amino acid-based chiral ionic liquids (CILs) as sole chiral selectors. Baseline separation was only achieved with sulfated CDs, and the best enantiomeric resolution was obtained with sulfated-γ-CD. Under the optimized conditions, ivabradine enantiomers were separated in 6 min with a resolution of 2.7. Nuclear magnetic resonance experiments showed a 1:1 stoichiometry for the enantiomer-CD complexes and apparent and averaged equilibrium constants were determined. The combined use of sulfated-γ-CD and different CILs as dual separation systems was investigated, resulting in a significant increase in the resolution. The use of 5 mM tetrabutylammonium-aspartic acid ([TBA][L-Asp]) in 50 mM formate buffer (pH 2.0) containing 4 mM sulfated-γ-CD were considered the best conditions in terms of resolution and migration times for ivabradine enantiomers. Nevertheless, as no inversion of the enantiomer migration order was observed when combining CILs and sulfated-γ-CD and a good enantiomeric resolution and efficiency were obtained using just sulfated-γ-CD as the sole chiral selector, the analytical characteristics of this method were evaluated, showing good recovery (98% and 103% for S- and R-ivabradine, respectively) and precision values (RSD < 5% for instrumental repeatability, < 6% for method repeatability and < 7% for intermediate precision). The limits of detection (LODs) were 0.22 and 0.28 µg mL-1 for S- and R-ivabradine, respectively, and the method enabled to detect a 0.1% of the enantiomeric impurity, allowing to accomplish the requirements of the International Conference on Harmonisation (ICH) guidelines. Finally, the method was applied to the analysis of a pharmaceutical formulation of ivabradine. The content of R-ivabradine was below the LOD and the amount of S-ivabradine was in agreement to the labeled content.


Assuntos
Aminoácidos/química , Química Farmacêutica/métodos , Cromatografia Capilar Eletrocinética Micelar , Ciclodextrinas/química , Líquidos Iônicos/química , Ivabradina/isolamento & purificação , Tampões (Química) , Ivabradina/química , Limite de Detecção , Estereoisomerismo , Sulfatos/química
6.
Pediatr Cardiol ; 40(6): 1284-1288, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31317219

RESUMO

Junctional ectopic tachycardia (JET) is the commonest tachyarrhythmia in the early post-operative period in children undergoing open-heart surgery. It frequently leads to hemodynamic instability and needs to be managed aggressively. Amiodarone is the first-line agent along with non-pharmacological interventions. We report our initial experience with the use of Ivabradine in post-operative JET. A retrospective case records review of children with post-operative JET during the period from June 2018 to May 2019 was performed. Eight patients with post-operative JET were treated with Ivabradine during this period. The first patient was initially treated with Amiodarone. All eight patients responded to Ivabradine. The initial response was rate control permitting overdrive pacing. One patient had recurrence of JET 10 h after Ivabradine and after return to sinus rhythm. Amiodarone was administered along with the second dose of Ivabradine resulting in remission to sinus rhythm. Ivabradine appears to be an effective alternative to Amiodarone in children with post-operative JET based on our initial clinical experience.


Assuntos
Fármacos Cardiovasculares/administração & dosagem , Ivabradina/administração & dosagem , Complicações Pós-Operatórias/tratamento farmacológico , Taquicardia Ectópica de Junção/tratamento farmacológico , Administração Intranasal , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do Tratamento
7.
Biomed Chromatogr ; 33(11): e4662, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31328807

RESUMO

We aimed to determine the pharmacokinetics and safety of three single oral doses (5, 10 and 15 mg) of ivabradine hemisulfate sustained-release tablets in healthy Chinese volunteers. A total of 12 volunteers (six males and six females) were randomized to receive a single oral dose of ivabradine hemisulfate sustained-release tablets 5, 10 or 15 mg, with a 1-week washout between periods. Blood samples were collected at regular intervals from 0 to 48 h after drug administration, and the concentrations of ivabradine and N-desmethyl ivabradine were determined by HPLC-tandem mass spectrometry. Pharmacokinetic parameters were estimated by non-compartmental analysis. After administering single doses of 5, 10 and 15 mg, the mean maximum concentration (Cmax ) levels of ivabradine were 4.36, 7.29 and 12.62 ng/mL, and the mean area under the curve from time 0 to 48 h (AUC0-48 ) values were 55.66, 101.16 and 182.09 h·ng/mL, respectively. The mean Cmax levels of N-desmethyl ivabradine were 1.05, 2.03 and 3.16 ng/mL, and the mean AUC0-48 values were 20.61, 39.44 and 65.72 h·ng/mL, respectively. The median time of maximum concentration (Tmax ) levels of ivabradine and N-desmethyl ivabradine were 5 h for all three doses tested. The pharmacokinetic properties of ivabradine hemisulfate sustained-release tablets were linear at doses from 5 to 15 mg. Ivabradine hemisulfate sustained-release tablet appears to be well tolerated in these healthy volunteers.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ivabradina/farmacocinética , Espectrometria de Massas em Tandem/métodos , Adulto , Grupo com Ancestrais do Continente Asiático , China , Feminino , Humanos , Ivabradina/administração & dosagem , Ivabradina/sangue , Limite de Detecção , Modelos Lineares , Masculino , Reprodutibilidade dos Testes , Comprimidos , Adulto Jovem
8.
Int Heart J ; 60(4): 899-909, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31308326

RESUMO

To systematically review and conduct a meta-analysis of the ivabradine-induced improvement in cardiopulmonary function, exercise capacity, and primary composite endpoints in patients with chronic heart failure (CHF).This study was a systematic review and meta-analysis.Databases, including PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Clinical Trials and European Union Clinical Trials, were searched for randomized placebo-controlled trials. The efficacy and safety of ivabradine treatment in patients with CHF were assessed and compared to those of the standard anti-heart failure treatment. Review Manager 5.3 software was used to analyze the relative risk (RR) for dichotomous data and the mean difference (MD) for continuous data.In total, 22 studies with 24,562 patients were included. Cardiopulmonary function analysis showed that treatment with added ivabradine reduced the heart rate (MD = -17.30, 95% confidence interval (CI): 19.52--15.08, P < 0.00001), significantly increased the left ventricular ejection fraction (LVEF) (MD = 3.90, 95% CI: 0.40-7.40, P < 0.0001), and led to a better New York Heart Association (NYHA) classification. Ivabradine significantly reduced the minute ventilation/carbon dioxide production (VE/VCO2) (MD = -2.68, 95% CI: -4.81--0.55, P = 0.01) and improved the peak VO2 (MD = 2.80, 95% CI: 1.05-4.55, P = 0.002) and the exercise capacity, including the exercise duration with a submaximal load (MD = 7.82, 95% CI: -2.57--18.21, P < 0.00001) and the 6-minute walk distance. The RR of cardiovascular death or worsening heart failure was significantly decreased (RR = 0.93, 95% CI: 0.87--0.98, P = 0.01) in the patients treated with ivabradine. Additionally, the RRs of heart failure and hospitalization also decreased (RR = 0.91, 95% CI: 0.85--0.97, P = 0.006; RR = 0.86, 95% CI: 0.79--0.93, P = 0.0002). Safety analysis showed no significant difference in the RR of severe adverse events between the ivabradine group and the standard anti-heart failure treatment group (P = 0.40). However, ivabradine significantly increased the RR of visual symptoms in CHF patients (RR = 3.82, 95% CI: 1.80--8.13, P = 0.0005).Existing evidence showed that adding ivabradine treatment significantly improved the cardiopulmonary function and increased the exercise capacity of patients with CHF. Adding ivabradine to the standard anti-heart failure treatment reduced the mortality and hospitalization risk and improved the quality of life. Finally, ivabradine significantly increased the RR of visual symptoms in CHF patients.This is the first systematic review and meta-analysis to focus on the efficacy of ivabradine, which improved the cardiac function and increased the exercise capacity in patients with chronic heart failure (CHF). Therefore, this study will help evaluate the quality of life after adding ivabradine to the treatment of patients with CHF, even though there are differences in the standard for resting heart rate, left ventricular ejection fraction (LVEF), and New York Heart Association (NYHA) class in the included studies. This hybrid effect might be smaller when analyzed separately but might have a higher heterogeneity when analyzed in multiple studies.


Assuntos
Tolerância ao Exercício/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Ivabradina/uso terapêutico , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/fisiopatologia , Humanos , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
9.
Rev Med Chil ; 147(3): 330-333, 2019 Mar.
Artigo em Espanhol | MEDLINE | ID: mdl-31344170

RESUMO

BACKGROUND: Pharmacological treatment improves survival in patients with heart failure with reduced ejection fraction. The use of sacubutril/valsartan and ivabradine has been recently approved and incorporated in the latest guidelines. AIM: To identify candidates eligible for these therapies among patients treated in a heart failure clinic, considering the inclusion criteria for the PARADIGM-HF and SHIFT trials. MATERIAL AND METHODS: Cross-sectional study on 158 patients aged 62 ± 11 years (67% male) with heart failure and reduced ejection fraction, with at least three months of follow-up and without decompensation. The percentage of patients complying for the inclusion criteria for the PARADIGM-HF y SHIFT trials was determined. RESULTS: In 37%, the etiology of heart failure was ischemic, 49% were in functional class I, their ejection fraction was 33 ± 11% and their median Pro-brain natriuretic peptide was 800 pg/mL. Ninety five percent were treated with vasodilators, 97% with beta-blockers and 82% with aldosterone antagonists. Using PARADIGM-HF and SHIFT criteria, 11 patients (7%) were eligible for sacubitril / valsartan and 21 patients (13.3%) for ivabradine. Among the main causes of non-eligibility for sacubitril / valsartan were being functional class I (48.7%) and not achieving a stable dose of enalapril ≥ 20 mg / day or losartan ≥ 100 mg / day (24.7%). In the case of ivabradine, apart from those in functional class I, the absence of sinus rhythm and a heart rate < 70 / min when receiving a maximal tolerated dose of beta-blockers, were present in 22%. CONCLUSIONS: A low percentage of our patients were eligible for these therapies. Among the causes that explain these results were clinical stability, a high percentage of patients in functional class I and being in a disease modifying treatment.


Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Fármacos Cardiovasculares/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Ivabradina/administração & dosagem , Tetrazóis/administração & dosagem , Idoso , Estudos Transversais , Relação Dose-Resposta a Droga , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes
10.
Mol Pharmacol ; 96(2): 259-271, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31182542

RESUMO

Abnormal cardiac electrical activity is a common side effect caused by unintended block of the promiscuous drug target human ether-à-go-go-related gene (hERG1), the pore-forming domain of the delayed rectifier K+ channel in the heart. hERG1 block leads to a prolongation of the QT interval, a phase of the cardiac cycle that underlies myocyte repolarization detectable on the electrocardiogram. Even newly released drugs such as heart-rate lowering agent ivabradine block the rapid delayed rectifier current IKr, prolong action potential duration, and induce potentially lethal arrhythmia known as torsades de pointes. In this study, we describe a critical drug-binding pocket located at the lateral pore surface facing the cellular membrane. Mutations of the conserved M651 residue alter ivabradine-induced block but not by the common hERG1 blocker dofetilide. As revealed by molecular dynamics simulations, binding of ivabradine to a lipophilic pore access site is coupled to a state-dependent reorientation of aromatic residues F557 and F656 in the S5 and S6 helices. We show that the M651 mutation impedes state-dependent dynamics of F557 and F656 aromatic cassettes at the protein-lipid interface, which has a potential to disrupt drug-induced block of the channel. This fundamentally new mechanism coupling the channel dynamics and small-molecule access from the membrane into the hERG1 intracavitary site provides a simple rationale for the well established state-dependence of drug blockade. SIGNIFICANCE STATEMENT: The drug interference with the function of the cardiac hERG channels represents one of the major sources of drug-induced heart disturbances. We found a novel and a critical drug-binding pocket adjacent to a lipid-facing surface of the hERG1 channel, which furthers our molecular understanding of drug-induced QT syndrome.


Assuntos
Canais de Potássio Éter-A-Go-Go/química , Canais de Potássio Éter-A-Go-Go/metabolismo , Ivabradina/farmacologia , Lipídeos de Membrana/metabolismo , Sítios de Ligação , Canais de Potássio Éter-A-Go-Go/genética , Humanos , Ivabradina/química , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Fenetilaminas/farmacologia , Ligação Proteica , Estrutura Terciária de Proteína , Sulfonamidas/farmacologia
13.
Life Sci ; 232: 116605, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254588

RESUMO

AIM: The present study was designed to investigate the possible role of T-type Ca2+ channels and HCN channels in the development of stress adaptation in cold-water immersion stress-subjected mice. MATERIAL AND METHODS: The mice were subjected to cold-water immersion stress by placing them individually in a water tank (depth = 15.5 cm; temperature = 15 ±â€¯2 °C) for 5 min. The mice were subjected to single episode of cold-water immersion stress for inducing acute stress; while for inducing stress adaptation, mice were subjected to repeated episodes of homotypic stressor (5 min) for 5 consecutive days. Animals were administered with ethosuximide (100 and 200 mg/kg, i.p.) and ivabradine (5 and 10 mg/kg, i.p.) before subjecting them to stress for five days. The stress-related behavioral alterations were assessed using the actophotometer, the hole board, the open field and the social interaction tests. The plasma corticosterone levels were quantified as a biochemical parameter of hypothalamic-pituitary-adrenal (HPA) axis activation. RESULTS: Acute stress altered the behavioral and biochemical parameters of the animals. However, repeated stress significantly restored the behavioral and biochemical alterations signifying the development of adaptation. Administration of ethosuximide and ivabradine abolished the restoration of behavioral and biochemical changes in the animals subjected to repeated stress. CONCLUSION: The ethosuximide and ivabradine mediated attenuation of stress adaptation demonstrates that the opening of T-type Ca2+ channels and activation of HCN channels are involved in inducing stress adaptation in repeated stress-subjected animals.


Assuntos
Canais de Cálcio Tipo T/fisiologia , Resposta ao Choque Frio/fisiologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/fisiologia , Aclimatação/fisiologia , Adaptação Fisiológica , Adaptação Psicológica/fisiologia , Animais , Comportamento Animal/fisiologia , Canais de Cálcio Tipo T/metabolismo , Temperatura Baixa , Corticosterona/sangue , Etossuximida/farmacologia , Sistema Hipotálamo-Hipofisário/fisiologia , Ivabradina/farmacologia , Camundongos , Sistema Hipófise-Suprarrenal/fisiologia , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia
14.
Cell Physiol Biochem ; 53(1): 36-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31169990

RESUMO

BACKGROUND/AIMS: Ivabradine lowers the heart rate by inhibition of hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels mediating the 'funny' pacemaker current If in the sinoatrial node. It is clinically approved for the treatment of heart failure and angina pectoris. Due to its proposed high selectivity for If administration of ivabradine is not associated with the side effects commonly observed following the application of other heart rate lowering agents. Recent evidence, however, has shown significant affinity of ivabradine towards Kv11.1 (ether-a-go-go related gene, ERG) potassium channels. Despite the inhibition of Kv11.1 channels by ivabradine, cardiac action potential (AP) duration and heart rate corrected QT interval (QTc) of the human electrocardiogram (ECG) were not prolonged. We thus surmised that compensatory mechanisms might counteract the drug's inhibitory action on Kv11.1. METHODS: The effects of ivabradine on human Kv11.1 and Kv7.1 potassium, Cav1.2 calcium, and Nav1.5 sodium channels, heterologously expressed in tsA-201 cells, were studied in the voltage-clamp mode of the whole cell patch clamp technique. In addition, changes in action potential parameters of human induced pluripotent stem cell (iPSC) derived cardiomyocytes upon application of ivabradine were studied with current-clamp experiments. RESULTS: Here we show that ivabradine exhibits significant affinity towards cardiac ion channels other than HCN. We demonstrate for the first time inhibition of human voltage-gated Nav1.5 sodium channels at therapeutically relevant concentrations. Within this study we also confirm recent findings of human Kv11.1 inhibition by low µM concentrations of ivabradine and observed no prolongation of ventricular-like APs in cardiomyocytes derived from iPSCs. CONCLUSION: Our results provide an explanation why ivabradine, despite its affinity for Kv11.1 channels, does not prolong the cardiac AP and QTc interval. Furthermore, our results suggest the inhibition of voltage-gated Nav1.5 sodium channels to underlie the recent observations of slowed atrioventricular conduction by increased atrial-His bundle intervals upon administration of ivabradine.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Canais Iônicos/metabolismo , Ivabradina/farmacologia , Canais de Cálcio Tipo L/química , Canais de Cálcio Tipo L/metabolismo , Linhagem Celular , Canal de Potássio ERG1/antagonistas & inibidores , Canal de Potássio ERG1/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Canais Iônicos/antagonistas & inibidores , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/química , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Técnicas de Patch-Clamp
16.
Expert Opin Drug Saf ; 18(5): 393-402, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31074301

RESUMO

INTRODUCTION: Heart failure with reduced ejection fraction (HFrEF) is associated with a worse outcome. Heart rate (HR) is related to outcome in HFrEF. Ivabradine selectively inhibits If (funny) channels in a concentration-dependent manner reducing HR. AREAS COVERED: The effects of ivabradine in HF were reviewed. The SHIFT trial results indicated that ivabradine improves chronic HFrEF outcomes, whereas published data suggest that amiodarone, digoxin, or verapamil may not be safe or the safety is controversial in HFrEF patients. In the CONSTATHE-DHF study, ivabradine reduced HR and improved left ventricular (LV) ejection fraction, LV diastolic functions, and right ventricle function in acute decompensated HF (ADHF). In chagasic patients, ivabradine reduced HR and a trend toward reduction in all-cause death was observed with ivabradine (p = 0.07). In children with HFrEF, ivabradine increased NYHA functional class. The most common side effects with ivabradine are bradycardia, atrial fibrillation, and phosphenes. Ivabradine was approved for HFrEF treatment by the EMA and FDA and seems to be cost-effective in HFrEF treatment. Ivabradine is indicated for HFrEF by the ESC HF Guidelines (IIa) and by the 2016 ACC/AHA/HFSA Guidelines (IIa-B-R). EXPERT OPINION: Published evidences demonstrate that ivabradine improves the outcome of chronic HFrEF and it seems to have a promising role in ADHF.


Assuntos
Fármacos Cardiovasculares/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Ivabradina/administração & dosagem , Animais , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/farmacologia , Relação Dose-Resposta a Droga , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Ivabradina/efeitos adversos , Ivabradina/farmacologia , Guias de Prática Clínica como Assunto , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
17.
Acta Crystallogr C Struct Chem ; 75(Pt 5): 545-553, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31062711

RESUMO

Ivabradine hydrochloride (IVA-HCl) (systematic name: {[3,4-dimethoxybicyclo[4.2.0]octa-1(6),2,4-trien-7-yl]methyl}[3-(7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)propyl]methylazanium), is a novel medication used for the symptomatic management of stable angina pectoris. In many recent patents, it has been claimed to exist in a very large number of polymorphic, hydrated and solvated phases, although no detailed analysis of the structural features of these forms has been published to date. Here, we have successfully crystallized the tetrahydrate form of IVA-HCl (form ß), C27H37N2O5+·Cl-·4H2O, and elucidated its structure for the first time. Simultaneously, a new crystal form of IVA-HCl, i.e. the hemihydrate (form II), C27H37N2O5+·Cl-·0.5H2O, was discovered. Its crystal structure was also accurately determined and compared to that of the tetrahydrate form. While the tetrahydrate form of IVA-HCl crystallized in the orthorhombic space group P212121, the new form (hemihydrate) was solved in the monoclinic space group P21. Detailed conformational and packing comparisons between the two forms have allowed us to understand the role of water in the crystal assembly of this hydrochloride salt. The stabilities of the two forms were compared theoretically by calculating the binding energy of the water in the crystal lattice using differential scanning calorimetry (DSC). The stability experiments show that the tetrahydrate is stable under high-humidity conditions, while the hemihydrate is stable under high-temperature conditions.


Assuntos
Fármacos Cardiovasculares/química , Ivabradina/química , Varredura Diferencial de Calorimetria , Estabilidade de Medicamentos , Ligações de Hidrogênio , Modelos Moleculares , Conformação Molecular , Termodinâmica , Água/química , Difração de Raios X
18.
PLoS One ; 14(5): e0217209, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31125368

RESUMO

BACKGROUND: Recently, attention has been focused on the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the mechanism of and as a treatment target for neuropathic and inflammatory pain. Ivabradine, a blocker of HCN channels, was demonstrated to have an effect on neuropathic pain in an animal model. Therefore, in the present study, we evaluated the effect of ivabradine on inflammatory pain, and under the hypothesis that ivabradine can directly influence inflammatory responses, we investigated its effect in in vivo and in vitro studies. METHODS: After approval from our institution, we studied male Sprague-Dawley rats aged 8 weeks. Peripheral inflammation was induced by the subcutaneous injection of carrageenan into the hindpaw of rats. The paw-withdrawal threshold (pain threshold) was evaluated by applying mechanical stimulation to the injected site with von Frey filaments. Ivabradine was subcutaneously injected, combined with carrageenan, and its effect on the pain threshold was evaluated. In addition, we evaluated the effects of ivabradine on the accumulation of leukocytes and TNF-alpha expression in the injected area of rats. Furthermore, we investigated the effects of ivabradine on LPS-stimulated production of TNF-alpha in incubated mouse macrophage-like cells. RESULTS: The addition of ivabradine to carrageenan increased the pain threshold lowered by carrageenan injection. Both lamotrigine and forskolin, activators of HCN channels, significantly reversed the inhibitory effect of ivabradine on the pain threshold. Ivabradine inhibited the carrageenan-induced accumulation of leukocytes and TNF-alpha expression in the injected area. Furthermore, ivabradine significantly inhibited LPS-stimulated production of TNF-alpha in the incubated cells. CONCLUSION: The results of the present study demonstrated that locally injected ivabradine is effective against carrageenan-induced inflammatory pain via HCN channels. Its effect was considered to involve not only an action on peripheral nerves but also an anti-inflammatory effect.


Assuntos
Fármacos Cardiovasculares/farmacologia , Carragenina/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Inflamação/prevenção & controle , Ivabradina/farmacologia , Dor/prevenção & controle , Canais de Potássio/metabolismo , Animais , Fármacos Cardiovasculares/administração & dosagem , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Ivabradina/administração & dosagem , Masculino , Dor/induzido quimicamente , Dor/metabolismo , Dor/patologia , Canais de Potássio/genética , Ratos , Ratos Sprague-Dawley
19.
BMJ Case Rep ; 12(4)2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31005863

RESUMO

Syncope is a sudden loss and gain of consciousness. Traditionally, it is caused by the abnormalities of neurological, cardiac or vasovagal systems. We present a case of a 19-year-old woman presenting with recurrent syncopal episodes with no apparent cause. Examination and investigations were unremarkable for any aetiology except positive tilt tests for postural orthostatic tachycardia syndrome. The purpose of this report is to make physicians aware of the unique presentation of this rare aetiology with recurrent syncopal episodes and the novel management approach.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Ivabradina/uso terapêutico , Síndrome da Taquicardia Postural Ortostática/tratamento farmacológico , Síncope/etiologia , Eletrocardiografia , Feminino , Humanos , Síndrome da Taquicardia Postural Ortostática/complicações , Síndrome da Taquicardia Postural Ortostática/diagnóstico , Teste da Mesa Inclinada , Adulto Jovem
20.
Medicine (Baltimore) ; 98(14): e15075, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30946357

RESUMO

BACKGROUND: Previous clinical trials have reported that ivabradine can effectively treat heart failure (HF). However, no systematic review has explored its efficacy and safety for HF. This systematic review will aim to evaluate the efficacy and safety of ivabradine for the treatment of patients with HF. METHODS: We will search the literature from the following electronic databases from inception to the January 31, 2019: Cochrane Central Register of Controlled Trials, EMBASE, MEDILINE, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, VIP Information, and Wanfang Data. All randomized controlled trials (RCTs) of ivabradine for HF will be fully considered for inclusion without any restrictions. Additionally, grey literature including clinical trial registries, dissertations, and reference lists of included studies, conference abstracts will also be searched. Two researchers will review these literatures, extract data, and assess risk of bias of included RCTs separately. Data will be pooled by either fixed-effects model or random-effects model, and meta-analysis will be conducted if it is appropriate. RESULTS: The primary outcome is all-cause mortality. The secondary outcomes comprise of change in body weight, urine output, change in serum sodium, and all adverse events. CONCLUSIONS: The results of this study will summary provide up-to-dated evidence for assessing the efficacy and safety of ivabradine for HF. ETHICS AND DISSEMINATION: It is not necessary to acquire ethical approval for this systematic review, because no individual patient data will be used in this study. The results of this systematic review will be published through peer-reviewed journals. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019120814.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Ivabradina/uso terapêutico , Revisão Sistemática como Assunto , China , Insuficiência Cardíaca/mortalidade , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA